DE3686677T2 - ISOXAZOLE AND FURAN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS AN ANTIVIRAL AGENT. - Google Patents

Description

The invention relates to isoxaols and furans with a phenylaliphatic side chain in which the phenyl group is substituted by an oxazole or a 1,3-oxazine group.

Sterling Drug Inc. discloses in EP-A-137,242, published on April 17, 1985, antiviral compounds having the formula

in which are:

R, R1, R2, R3 and R4 are each hydrogen or alkyl of 1 to 3 carbon atoms optionally substituted by hydroxy, lower alkanoyloxy, lower alkoxy, chlorine or N=Z wherein N=Z is amino, lower alkanoylamino, lower alkylamino, di-lower alkylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-morpholinyl with the proviso that R is not hydrogen;

R�5 is hydrogen, lower alkyl, halogen, nitro, lower alkoxy, lower alkylthio or trifluoromethyl;

X is O or a single bond and n is an integer from 3 to 9;

as well as the pharmaceutically acceptable acid addition salts of that.

It has been found that related compounds in which the phenyl ring is substituted by selected substituents in both positions adjacent to the isoxazole-bearing side chain generally have improved properties compared to the corresponding monosubstituted or unsubstituted compounds.

Accordingly, the present invention relates to compounds of the formula

in which are:

R is hydrogen or alkyl having 1 to 3 carbon atoms optionally substituted by hydroxy or alkoxy having 1 to 4 carbon atoms;

X is O or CH₂;

Y is an alkylene bridge with 3 to 9 carbon atoms or an olefin chain of 5 carbon atoms with an unsaturated bond;

Z is N or R₅C, wherein R₅ is hydrogen or an alkanoyl having 1 to 4 carbon atoms provided that R is not hydrogen when Z is N;

m O or 1;

R₁ and R₂ are each halogen, methyl, nitro or trifluoromethyl and

R₃ and R₄ are each hydrogen or lower alkyl having 1 to 3 carbon atoms or their pharmaceutically acceptable acid addition salts.

The dashed line in the oxazole or 1,3-oxazine ring shows that a double bond can optionally be present in the indicated position.

A preferred class of compounds within the scope of formula I are those having the following formula:

in which are:

m 0 or 1;

R is methyl or hydroxymethyl;

R₁ and R₂ are each halogen, methyl, nitro or trifluoromethyl and

R₃ and R₄ each represent hydrogen or lower alkyl having 1 to 3 carbon atoms and the pharmaceutically acceptable acid addition salts thereof.

A preferred species within the framework of formula II is 5- {5[2,6-dichloro-4(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}isoxazole with (m = 0, R = CH₃, R₁ and R₂ = Cl, R₃ and R₄ = H).

Compositions for combating viruses comprise an antivirally effective amount of a compound of formula I or II in admixture with a suitable carrier or diluent.

Compounds of formula I in which X is oxygen can be prepared by reacting a compound of formula

wherein Hal is chlorine, bromine or iodine, is reacted with an alkali metal salt of a compound of the formula

Likewise, a compound of the formula without a double bond in the 4,5-position of the oxazole or 5,6-oxazine ring can be prepared, wherein R is hydrogen or lower alkyl having 1 to 3 carbon atoms and upon ring closure a compound of the formula

wherein Hal' is chlorine or bromine, by heating the latter in an inert solvent in the presence of an acid acceptor.

Novel antiviral intermediates of formula III are also disclosed.

The compounds of formulas I and II are sufficiently basic to form stable acid addition salts with strong acids, which salts are within the scope of the invention. The nature of the acid addition salt is insignificant provided it is derived from an acid whose anions are essentially non-toxic to the animal organism. Examples of suitable acid addition salts include the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, maleate, citrate, tartrate, methanesulfonate, p-toluenesulfonate, dodecyl sulfate and cyclohexane sulfamate.

Throughout this specification and claims, the use of such terms as "lower alkyl", "lower alkoyl" or "lower alkanoyl" refers to groups containing between 1 and 4 carbon atoms. Throughout this specification and claims, when the term halogen is used to define the substituents R₁ and R₂, it is understood to mean any of the four common halogens fluorine, chlorine, bromine or iodine, with chlorine and bromine being preferred.

The process for preparing the compounds of formula I wherein X is oxygen by reacting a compound of formula

with a compound of the formula

was carried out by heating the reactants in an inert solvent in the presence of an alkali metal base, e.g. potassium carbonate, at a temperature between about 50 ºC and 150 ºC.

The intermediates of formula IV, where Z is N, are prepared by reacting an alkali metal derivative of an isoxazole of the formula

wherein R is alkyl or hydroxyalkyl of 1 to 3 carbon atoms with a dihalide, Hal-Y'-Hal, where Y' is an alkylene bridge of 2 to 8 carbon atoms which may optionally be interrupted by an olefin linkage. This alkali metal derivative was prepared in situ by treating the compound of formula VI with an organic alkali metal base under anhydrous conditions. Preferred organic alkali metal bases are butyllithium and lithium diisopropylamide.

The intermediates of formula IV, where Z is R8C, are prepared from the appropriate omega-(2-furan)alkanoic acid by reduction to the corresponding alcohol and replacement of the hydroxy group with halogen, or by direct alkylation of the furan with a dihalide, Hal-Y-Hal, in the presence of a strong base such as butyllithium.

The intermediates of formula VI are a well-known class of oxazole-substituted phenols, which are prepared according to the general description and specific examples below.

The following flow chart shows the preferred synthetic procedures for the preparation of 4,5-dihydrooxazoles. Hydrolysis acid acceptor

A hydroxybenzoate (VII, Alk = lower alkyl) was condensed with a hydroxyalkylamine to give a hydroxyalkylamide (VIII). The latter was then cyclized with thionyl chloride to give a substituted phenol of formula IX. The final step is the reaction of the phenol with an alkylisoxazole or -furan already described above.

Alternatively, the hydroxybenzoate (VII) was reacted with a haloalkylisoxazole or furan to give the ester (X) which was hydrolyzed to the corresponding acid (XI). The latter was then converted to its acid chloride (XII) which was reacted with a chloroalkylamine to give a chloroalkylamide intermediate of formula III (X = 0). The latter was reacted upon heating in the presence of an acid acceptor to give a final product of formula I (X = 0). The latter ring closure took place in an inert solvent at a temperature between 50 °C and 150 °C, conveniently at the reflux temperature of the solvent mixture. The acid acceptor can be any basic substance capable of absorbing the hydrogen chloride produced in the reaction while on the other hand being inert in the reaction. Such acid acceptors can be tertiary amines or inorganic bases such as potassium carbonate. A preferred acid acceptor is 1,8-diazabicyclo(5.4.0)undec-7-ene.

Variations in the sequence of steps VII to X to XI can be achieved by using compounds with nitrile or formyl groups instead of the ester groups with a possible conversion to the free carboxyl groups.

The compounds of formulas I and II having a double bond in the 4,5-position of the oxazole ring were prepared by a process analogous to that described above, namely by reaction of a phenol of the formula

with a compound of formula IV. The intermediates of formula XIII were in turn prepared by reacting an aldehyde of formula

with an oxime of the formula R₃C(=NOH)-COR₄ and reduction of the resulting oxazole N-oxide with zinc or titanium trichloride.

Compounds of formula I where X is CH2 were prepared by alkylation of a compound of formula

with a haloalkylisoxazole or furan of formula IV and gave an ester of formula

The ester group of formula XIV was then modified by procedures analogous to the reaction sequence x → XI → XII → III → I to form the oxazole or oxazine ring.

The compounds of formula I in which R is a lower alkyl substituted by methoxy are particularly easily prepared from the corresponding compounds of formula I in which R is hydroxyalkyl.

Etherification of a hydroxyalkyl compound by conventional methods, such as reaction with a lower alkyl halide in the presence of a strong base, afforded the corresponding lower alkoxy derivatives.

A hydroxyalkyl compound can be converted to a haloalkyl compound by reaction with a reagent such as thionyl halite or phosphorus trihalite, which can replace aliphatic hydroxy groups with halogen.

The haloalkyl compounds are in turn convertible into aminoalkyl compounds by reaction with ammonia or an amine, HN=Z'. Compounds in which HN=Z' is a lower alkanoylamino were prepared by acylation of the compounds in which HN=Z' is NH2 with a lower alkanoyl halide or anhydride, the lower alkanoyl preferably having 1 to 4 carbon atoms.

The structures of the compounds of the invention were determined by the types of synthesis, by elemental analysis and by infrared and NMR spectra.

The following examples are intended to further illustrate the invention.

example 1 a) 3,5-dichloro-4-hydroxy-N-(2-hydroxyethyl)benzamide

(VIII; R₁ and R₂ = Cl, R₃ and R₄ = H, m = O) A 2-liter three-necked round-bottom flask was charged with 2-aminoethanol (240 g, 3.93 mol) and heated to 80 ºC. Methyl 3,5-dichloro-4-hydroxybenzoate (432 g, 1.96 mol) was added portionwise to the powder funnel. The resulting amber solution was heated to 145 °C and the methanol liberated distilled into a Dean Stark receiver. The reaction took about 3 1/2 hours. After completion, the solution was cooled to 90 °C . . . 100 °C and dissolved in 1.95 liters of water. The aqueous solution was cooled to 25 °C, placed in an ice bath and slightly acidified with concentrated hydrochloric acid (196 mL, 2.35 mol). The product precipitated and gave a white residue upon filtration. After drying at 50 °C in a vacuum oven, the product darkened slightly. The crude material (384.4 g, 78.8%) was ground and passed through a No. 20 sieve to afford 3,5-dichloro-4-hydroxy-N-(2-hydroxyethyl)benzamide as a cream solid (m.p. 174 ºC . . . 178 ºC) suitable for use in the next step.

b) 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol

(IX; R₁ and R₂ = Cl, R₃ and R₄ = H, in = O)

3,5-Dichloro-4-hydroxy-N-(2-hydroxyethyl)benzamide (400 g, 1.61 mol) was ground before use and passed through a No. 20 sieve. To a stirred suspension of the above in 2.8 L of isopropyl acetate was added thionyl chloride (285 g, 2.41 mol) in a stationary stream.

An exothermic reaction developed up to 45 ºC . . . 50 ºC, and after a short time the gray suspension appeared lighter. After stirring for 2 1/2 hours, the suspension was cooled to room temperature and filtered. The filter cake was washed with isopropyl acetate and dried in a vacuum oven at room temperature overnight. There were obtained 371 g (86% yield) of 2,6-dichloro-4-(4,5- dihydro-2-oxazoly)phenol in the form of its hydrochloric acid salt, m.p. 189 ºC . . . 191 ºC, suitable for use in the next step. The purified free base has a melting point of 195 ºC (decomposition).

c) 5-{5-2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole (II; R = CH₃, R₁ and R₂ = Cl, R₃ and R₄ = H, m = O)

To a stirred suspension of ground potassium carbonate (172.5 g, 1.25 mol) in 1.35 L of dimethylformamide (DMF) was added 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol hydrochloride (133.5 g, 0.5 mol). Vigorous gas evolution (CO2) occurred as the reaction was heated to 70°C on a steam bath. After stirring for about 5 minutes, 5-(5-bromopentyl)-3-methylisoxazole (121.8 g, 0.525 mol) was added in one portion. The mixture was heated to 90°C...95°C for one hour, cooled to room temperature, and then filtered. The filter cake was washed with DMF and the filtrate was concentrated with a water aspirator under vacuum to a viscous brown oil (260 g). The residue was dissolved in 300 mL of isopropyl acetate and washed with water and then brine. The organic layer was dried over magnesium sulfate, treated with charcoal, filtered and evaporated to dryness. The crude product (220 g oil) was diluted with 287 mL of acetone (1.5 volume based on theoretical yield) and cooled to -25 ºC and stirred in a dry ice/acetone bath. The product was collected and air dried to afford 115 g (60% yield) of 5-{5-[2,6-dichloro-4-(4,5-dihydro 2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole, mp 38 ºC...40 ºC. A sample was recrystallized from triethylamine and had a melting point of 42 ºC . . . 43 ºC. The 5-{52,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole formed an acid addition salt with a melting point of 98 ºC . . 101 ºC on treatment with methanesulfonic acid. The intermediate 5-(5-bromopentyl)-3-methylisoxazole was prepared from 1,4-dibromobutane and the lithium salt of 3,5-dimethylisoxazole was reacted in situ with n-butyllithium and Diisopropylamine in tetrahydrofuran solution.

Following the procedure described above in Example 1, the following compounds were prepared:

Example 2 5-{5-[4-(4,5-Dihydro-2-oxazolyl)-2.6-dimethylphenoxylpentyl}-3-methylisoxazol

(II; R, R1 and R2 = CH3, R3 and R4 = H, m = 0), amber, by chromatography, melting point below room temperature, monomethanesulfonate salt: m.p. 114 ºC . . . 115 ºC Intermediates: 5-(5-bromopentyl)-3-methylisoxazole and 4-(4,5-dihydro-2-oxazolyl)-2,6-dimethylphenol hydrochloride salt, m.p. 208 ºC . . . 210 ºC (from methanol).

Example 3 5-{5-[2,6-Dibromo-4-(4,5-dihydro-2-oxazolyl)phenoxypentyl[- 3-methylisoxazole

(II; R = CH₃, R₁ and R₂ = Br, R₃ and R₄ = H, m = 0), light yellow oil by chromatography, melting point below room temperature.

Intermediates: 5-(5-bromopentyl)-3-methylisoxazole and 2,6-dibromo-4-(4,5-dihydro-2-oxazolyl)phenol hydrochloride, again prepared by ring closure of 3,5-dibromo-4-hydroxy-N-(2-hydroxyethyl)benzamide (VIII; R1 and R2 = Br, R3 and R4 = H, m = 0), mp 172 ºC . . . 173 ºC.

Example 4 5-{6-[2,6-dichloro-4-4(4,5-dihydro-2-oxazolyl)phenoxylhexyl}-3-methylisoxazole

(I; Y = (CH₂)₆, X = 0, Z = N, m = 0, R = CH₃, R₁ and R₂ = Cl, R₃ and R₄ = H), F 48 ºC . . . 50 ºC (from triethylamine).

Intermediates: 5-(6-bromohexyl)-3-methylisoxazole and 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol (Example 1b).

Example 5 5-{5-[2,6-Dichloro-4-(4,5-dihydro-4-methyl-2-oxazolyl)phenoxyl]pentyl}-3-methylisoxazole

(II; R = CH₃, R₁ and R₂ = Cl, R₃ = CH₃, R₄ = H, m = 0), viscous yellow oil by chromatography, melting point below room temperature.

Intermediates: 5-(5-bromopentyl)-3-methylisoxazole and 2,6-dichloro-4-(4,5-dihydro-4-methyl-2-oxazolyl)phenol, m.p. 145 ºC . . . 146 ºC, again prepared from 3,5-dichloro-4- hydroxy-N-(2-hydroxy-l-methylethyl)benzamide, m.p. 168 ºC . . . 170 ºC (from acetonitrile).

Example 6 5-{5-[2,6-Dichloro-4-(4,5-dihydro-5-methyl-2-oxazolyl)phenoxylpentyl}-3-methylisoxazole

(II, R = CH₃, R₁ and R₂ = Cl, R₃ = H, R₄ = CH₃, m = 0), yellow oil, by chromatography, melting point below room temperature.

Intermediates: 5-(5-bromopentyl)-3-methylisoxazole and 2,6- dichloro-4-(4,5-dihydro-5-methyl-2-oxazolyl)-phenol, m.p. 173 ºC . . . 174 ºC, again prepared from 3,5-dichloro-4-hydroxy- N-(2-hydroxypropyl)benzamide, m.p. 126 ºC . . . 128 ºC (from isopropyl acetate).

Example 7 5-{5-[2,6-Dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]hexyl}- 3-methylisoxazole

(I; Y = CH₂CH₂CH₂CH₂CH(CH₃), X = 0, Z = N, m = 0, R = CH₃, R₁ and R₂ = Cl, R₃ and R₄ = H), colorless oil, by chromatography.

Intermediates: 5-(5-bromohexyl)-3-methylisoxazole and 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol.

Example 8 5-{4-[2,6-Dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}- 3-methylisoxazole

(I; Y = CH₂CH₂CH₂CH₂CH(CH₃), X = 0, Z = N, m = O, R = CH₃, R₁ and R₂ = Cl, R₃ and R₄ = H), yellow oil, by chromatography.

Intermediates: 5-(4-bromopentyl)-3-methylisoxazole and 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol.

Example 9 5-{5-[2-Bromo-4-(4,5-dihydro-2-oxazolyl)-6-nitrophenoxy]pentyl}-3-methylisoxazole

(II; R = CH₃, R₁ = Br, R₂ = NO₂, R₃ and R₄ = H, m = 0), yellow oil, by chromatography.

Intermediates: 5-(5-bromopentyl)-3-methylisoxazole and 2-bromo-4-(4,5-dihydro-2-oxazolyl)-6-nitrophenol. The latter is a light yellow solid and was prepared by ring closure of 3-bromo-4-hydroxy-N-(2-hydroxyethyl)-5-nitrobenzamide, yellow solid, mp 163ºC . . . 164ºC (from methanolisopropyl acetate). The latter was in turn prepared by bromination of 4-hydroxy-3-nitrobenzoic acid to form 5-bromo-4-hydroxy-3-nitrobenzoic acid, mp 233ºC . . . 234ºC (yellow solid from isopropyl acetate), esterification to the corresponding methyl ester, mp 128ºC . . . 130 ºC (yellow solid substance of carbon tetrachloride), and reaction of the latter with 2-hydroxyethylamine.

Example 10 5-{5-[2,6-Dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]-3- pentenyl}-3-methylisoxazole (Z-isomer)

I; Y = (CH2)2CH=CHCH2, X = O, Z = N, m = 0, R = CH3, R1 and R2 = Cl, R3 and R4 = H), colorless solid, mp 52ºC 54ºC (from t-butyl methyl ether).

Intermediates: 2,6-dichloro-4-(4,5-dihydro-2oxazolyl)phenol and the isomer of 5-(5-chloro-3-pentenyl)-3- methylisoxazole, prepared from cis-1,4-dichloro-2-butene and 3,5-dimethylisoxazole.

Example 11 5-{5-[2,6-Dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]-3- pentenyl}-3-methylisoxazole (E-isomer)

(I; Y = (CH2)2CH=CHCH2, X = O, Z = N, m = 0, R = CH3, R1 and R2 = Cl, R3 and R4 = H), colorless solid, mp 59ºC 61ºC (from ether-hexane).

Intermediates: 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol and the isomer of 5-(5-chloro-3-pentenyl)-3- methylisoxazole, prepared from trans-1,4-dichloro-2-butene and 3,5-dimethylisoxazole.

Example 12 5-{7-[2,6-Dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}- 3-methylisoxazole

(I; Y = (CH2)7, X = O, Z = N, m = 0, R = CH3, R1 and R2 = Cl, R3 and R4 = H), colorless solid, mp 36ºC . . . 37ºC (from ether- -hexane) Intermediates: 5-(7-bromoheptyl)-3-methylisoxazole and 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol.

Example 13 5-{3-[2,6-Dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]propyl}- 3-methylisoxazole

(I; Y = (CH₂)₃, X = O, Z = N, m = 0, R = CH₃, R₁ and R₂ = Cl, R₃ and R₄ = H), colorless solid, mp 67 ºC . . . 68 ºC (from ether)

Intermediates: 5-(3-iodopropyl)-3-methylisoxazole and 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol.

Example 14 2-{3,5-Dichloro-4-[5-(2-furanyl)pentyloxy]phenyl}-4,5- dihydrooxazole

(I; Y = (CH₂)₅, X = 0, Z = HC, m = 0, R = H, R₁ and R₂ = Cl,

R₃ and R₄ = H), amber oil by chromatography.

Intermediates: 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol and 2-(5-bromopentyl)furan, prepared from furan and 1,5-dibromopentane.

Example 15 a) 4-(2-furanyl)-1,4-butadiene 1,1-dicarboxylic acid

A mixture of 122.1 g of 2-furanacrolein, 225 g of malonic acid, 330 mL of pyridine and 0.5 mL of piperidine was stirred over a steam bath for four hours. The reaction mixture was concentrated in vacuo, 1 liter of water was added and the mixture was acidified with 6N hydrochloric acid. The yellow solid product (120 g) was collected, washed with water, dried and used immediately in the next reaction.

b) 5-(2-furanyl)pentanoic acid

The acid from section (a) was dissolved in aqueous potassium hydroxide and hydrogenated in the presence of 2 g of palladium/carbon catalyst for four hours. The hydrogenated product was acidified, separated and refluxed with 150 mL of pyridine for eleven hours to effect decarboxylation. The resulting product was separated and distilled to afford 60.4 g of 5-(2-furanyl)pentanoic acid, b.p. 105 °C . . . 120 °C (0.07 min).

c) 5-(2-furanyl)pentanol

5-(2-furanyl)pentanolic acid (60.4 g) was heated with 13.7 g of lithium aluminum hydride in 400 mL of tetrahydrofuran under reflux for about 16 hours. The product was isolated and purified by distillation to yield 51.4 g of 5-(2-furanyl)pentanol, b.p. 70 ºC . . . 73 ºC.

d) 5-(2-furanyl)pentanol acetate

5-(2-furanyl)pentanol (81.8 g) was esterified with 100 mL of acetic anhydride and 200 mg of dimethylaminopyridine to give 97.0 g of the acetate ester, b.p. 74 ºC . . . 75 ºC.

e) 5-(6-Acetyl-2-furanyl)pentanol acetate

To a mixture of 100 ml of trifluoroacetic anhydride and 100 ml of glacial acetic acid was added 89 g of 5-(2-furanyl)pentanol acetate in 100 ml of acetic acid. The reaction mixture was left at room temperature for 16 hours and then poured into water and extracted with methylene dichloride. The extracts were concentrated and the residue distilled to give 60.6 g of 5-(6-acetyl-2-furanyl)pentanol acetate, b.p. 120 ºC . . . 123 ºC (0.05 mm).

f) 5-(6-acetyl-2-furanyl)pentanol

5-(6-Acetyl-2-furanyl)pentanol acetate (60.6 g) was hydrolyzed with 3 g of sodium ethoxide in 900 mL of absolute methanol and the product was isolated to give 37.3 g of 5-(6- Acetyl-2-furanyl)pentanol, b.p. 132 ºC . . . 135 ºC (0.1 mm).

g) 2-(5-chloropentyl)-6-aceylfuran

(IV; Z = CH3COC, Hal = Cl, R = H, Y = (CH2)5) 5-(6-Acetyl-2-furanyl)pentanol (9.8 g), 13.1 g triphenylphoshine and 100 mL carbon tetrachloride were mixed and heated under reflux for four hours. The reaction mixture was concentrated in vacuo and the residue dissolved in ether and filtered. The filtrate was concentrated and the residue distilled twice to afford 2-(5-chloropentyl)-6-acetylfuran, b.p. 100 °C 102 °C (0.05 mm) in 60% yield.

h) 2-{3,5-Dichloro-4-[5-(6-acetyl-2-furanyl)pentyloxy]phenyl}-4,5-dihydrooxazole

(I; Y = (CH₂)₅), X = 0, Z = CH₃COC, m = 0, R = H, R₁ and R₂ = Cl, R₃ and R₄ = H)

This compound can be prepared by reaction of 2-(5- Chloropentyl)6-acetylfuran with 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol in the presence of potassium carbonate and sodium iodide according to the general procedures of Example 1, part (c).

Example 16 5-{5-[2,6-Dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]phenyl}- 3-isoxazolemethanol

(II; R = HOCH₂, R₁ and R₂ = Cl, R₃ and R₄ = H, m = 0), colourless solid, mp 65 ºC . . . 66 ºC (from hexane- isopropyl acetate).

Intermediates: 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol and 5-(5-chloropentyl)-3-hydroxymethylisoxazole, prepared from 3-hydroxymethyl-5-methylisoxazole and 1- chloro-4-bromobutane.

Example 17 5-{5-[2,6-Dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}- 3-isoxazolylmethyl-methyl-dimethylglyoxalate

(I; Y = (CH₂)₅, X = 0, Z = N, m = 0, R = H₃COOC(CH₂)2COOCH₂, R₁ and R₂ = Cl, R₃ and R₄ = H)

To a solution of 5.0 g of 5-{5-[2,6-dichloro-4-(4,5- dihydro-2-oxazolyl)phenoxy]pentyl}-3-isoxazolemethanol (Example 16), 1.75 g of monomethyl succinate and a catalytic amount of p-dimethylaminopyridine in 100 mL of chloroform was added 2.6 g of dicyclohexylcarbodiimide at 0 ºC. The reaction mixture was stirred at room temperature for 24 hours and then filtered and concentrated to provide 4.5 g of the product which upon recrystallization from hexane-isopropyl acetate gave 4.2 g of 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]penty}-3-isoxazolylmethylmethyldimethylglyoxalate, mp 39 °C . . . 41 °C.

Example 18 5-{5-[2,6-Dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-(methoxymethyl)isoxazole

(I; Y = (CH₂)₅, X = 0, Z = N, m = 0, R = CH₃OCH₂, R₁ and R₂ = Cl, R₃ and R₄ = H)

To a solution of 6.8 g of 5-{5-[2,6-dichloro-4-(4,5- dihydro-2-oxazolyl)phenoxy]pentyl}-3-isoxazolemethanol (Example 16) in 100 mL of dry tetrahydrofuran was added 0.45 g of sodium hydride. After completion of the hydrogen evolution, the solution was cooled in an ice bath and 1.1 mL of methyl iodide was added. The reaction mixture was stirred at room temperature for 48 hours and diluted with ether and washed sufficiently with water. Evaporation of the solvent and chromatography provided 3.1 g of the product as a viscous yellow oil.

Example 19 a)5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-isoxazolylmethoxyinethoxyethyl acetate

(I; Y = (CH₂)5, X = 0, Z = N, m = 0, R = CH₃CO(CH₂)₂OCH₂OCH₂, R₁ and R₂ = Cl, R₃ and R₄ = H)

This compound was prepared from 4.0 g of 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-isoxazolemethanol (Example 16) and 2.0 g of 2-acetoxyethoxymethyl bromide (CH3COCH2CH2OCH2Br) in the presence of sodium hydride according to the procedure of Example 18 and was obtained as a colorless oil (2.4 g).

b) 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-isoxazolylmethoxymethoxyethanol

(I; Y = (CH₂)₅, X = 0, Z = N, m = 0, R = HO(CH₂)₂OCH₂OCH₂, R₁ and R₂ = Cl, R₃ and R₄ = H)

This compound was prepared by hydrolysis of the acetate from section (a) with lithium hydroxide in methanol for 12 hours at room temperature and was obtained as a pale yellow oil (2.8 g).

It is further believed that 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-isoxazolemethanol (Example 16) can be reacted with thionyl chloride to afford 3-chloromethyl-5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}isoxazole (I; Y = (CH2)5, X = 0, Z = N, m = 0, R = ClCH2, R1 and R2 = Cl, R3 and R4 = H), and that the latter in turn can be reacted with ammonia or an amine, e.g. B. ethylamine, dimethylamine, pyrrolidine, piperidine or morpholine to yield the corresponding compounds having a 3- aminomethyl, 3-ethylaminomethyl, 3-dimethylamino, 3-(1- pyrrolidyl)methyl, 3-(1-piperidinyl)methyl or 3-(4-morpholinyl)methyl group.

Example 20

Hydrogen chloride gas was bubbled through a mixture of 13.45 g of 3,5-dimethyl-4-hydroxybenzaldehyde and 9.3 g of 2,3-butanedione monooxime in 66.7 ml of glacial acetic acid for 11 minutes. The reaction mixture was kept at room temperature overnight and the solid product was collected, washed with ether and dried to give 14.86 g of 4-(4,5-dimethyl-2-oxazolyl)-2,6-dimethylphenol N-oxide in the form of its hydrogen chloride salt with a melting point of 198 °C . . . 201 °C.

b) 4-(4,5-dimethyl-2-oxazolyl)-2,6-dimethylphenol

(IX; R₁, R₂, R₃ and R₄ = CH₃, m = 0)

To a mixture of 14.86 g of 4-(4,5-dimethyl-2-oxazolyl)-2,6-dimethylphenol-N-oxide hydrochloride and 220 ml of glacial acetic acid, 28 g of zinc dust were added in portions while stirring at 100 ºC. The reaction mixture was stirred at 100 ºC for 1 1/2 hours and kept at room temperature for three days. The product was isolated by separating between ethyl acetate and water. From the ethyl acetate fraction, 11 g of the product were obtained, which was obtained from acetonitrile. was recrystallized to give 7.31 g of 4-(4,5-dimethyl-2-oxazolyl)-2,6-dimethylphenol, mp 203 ºC . . . 205 ºC.

c) 5-{5-[4-(4,5-dimethyl-2-oxazolyl)-2,6-dimethylphenoxy]pentyl}-3-methylisoxazole

(II; R, R₁, R₂, R₃ and R₄ = CH₃, m = 0), hydrochloride salt, m.p. 136ºC and 140ºC (colorless granules from ethanol), prepared from 4-(4,5-dimethyl-2-oxazolyl)-2,6-dimethylphenol and 5-(5-bromopentyl)-3-methylisoxazole.

Example 21 a) 2-(3,5-dichloro-4-hydroxyphenyl)-4,5-dimethyloxazole-N-oxide

The compound was prepared from 19.1 g of 3,5-dichloro-4-hydroxybenzaldehyde and 10.1 g of butanedione monooxime in formic acid in the presence of hydrogen chloride gas. 12.2 g of the product were obtained, mp 221 ºC . . . 223 ºC.

b) 3,5-dichloro-4-(4,5-dimethyl-2-oxazolyl)phenol

(IX; R₁ and R₂ = Cl, R₃ and R₄ = CH₃, m = 0)

A solution of titanium trichloride (20%, 100 mL) was added dropwise over 30 minutes to a stirred mixture of 16.0 g of the N-oxide from section (a) in 1000 mL of tetrahydrofuran. The product was isolated to give 9.0 g of 3,5-dichloro-4-(4,5-dimethyl-2-oxazolyl)phenol, mp 228 ºC . . . 229 ºC.

c) 5-{5-[2,6-dichloro-4-(4,5-dimethyl-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole

(II; m = 0, R = CH3, R1 and R2 = Cl, R3 and R4 = CH3), mp 61ºC . . . 62ºC (colorless solid from triethylamine). This compound was prepared from 3,5-dichloro-4-(4,5- dimethyl-2-oxazolyl)phenol and 5-(5-bromopentyl)-3-methylisoxazole.

Example 22 5-{4-[2,6-Dichloro-4-(4,5-dimethyl-2-oxazolyl)phenoxy]butyl}- 3-methylisoxazole

(I; Y = (CH₂)₄, X = 0, Z = N, m = 0, R = CH₃, R₁ and R₂ = Cl, R₃ and R₄ = CH₃), mp 64 ºC . . . 65 ºC (from ether-hexane).

This compound was prepared from 3,5-dichloro-4- (4,5-dimethyl-2-oxazolyl)phenol (Example 21b) and 5-(4-bromobutyl-3-methylisoxazole.

Example 23 5-{-5-[2,6-dichloro-4-(2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole

(II; R = CH₃, R₁ and R₂ = Cl, R₃ and R₄ = H, m = 0), light brown powder, mp 39 ºC . . . 41 ºC (from ether-hexane).

Example 24 a) Methyl 3-bromo-5-chloro-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}benzoate

(IX; Y = (CH₂)₅, Z = N, R = CH₃, Rl = Cl, R₂ = Br, Alk = CH₃

The compound was prepared from 41.3 g of methyl 3-bromo-5-chloro-4-hydroxybenzoate (prepared by bromination of 3-chloro-4-hydroxybenzoic acid and esterification), 40.6 g of 5-(5-bromopentyl)-3-methylisoxazole, 61.7 g of potassium carbonate and 0.2 g of sodium iodide in 500 ml of dimethylformamide at 90 °C...95 °C for three hours and was obtained as a colorless oil after chromatography on silica.

b) 3-Bromo-5-chloro-N-(2-chloroethyl)-4-{5-(3-methyl-5-isoxazolyl)pentyl]oxy}benzoic acid

(XI; Y = (CH₂)₅, Z = N, R = CH₃, R₁ = Cl, R₂ = Br)

This compound was prepared by hydrolysis of 51.3 g of the ester from section (a) with 3.1 g of lithium hydroxide in 500 mL of methanol and 10 mL of water by heating under reflux overnight. The reaction mixture was diluted, acidified and extracted with ethyl acetate. From the latter 42.8 g of the product with a melting point of 104 ºC 105 ºC was obtained after recrystallization from ether-hexane.

c) 3-Bromo-5-chloro-N-(2-chloroethyl)-4-{[5-(3-methyl-5- isoxazolyl)pentyl]oxy}benzamide

(III; X = 0, Y = (CH₂)₅, Z = N, m = 0, R = CH₃, R₁ = Cl, R₂ = Br, R₃ and R₄ = H, Hal' = Cl)

The acid from section (b) (29.2 g) was stirred with an excess of thionyl chloride (about 35 mL) for about 16 hours. The unreacted thionyl chloride was evaporated and 250 mL of chloroform was added followed by 21 g of 2-chloroethylamine hydrochloride. This mixture was cooled to 0 °C and 80 mL of triethylamine was added dropwise. The reaction mixture was stirred overnight, then diluted with chloroform and washed with dilute hydrochloric acid. From the chloroform solution, 30.9 g of product was obtained with sufficient purity for use in the next step. A sample of the compound had a melting point of 84 °C . . . 86 °C after purification by chromatography and recrystallization from isopropyl alcohol.

d) 5-{5-[2-bromo-6-chloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole

(II; R = CH₃, R₁ = Cl, R₂ = Br, R₃ and R₄ = H, m = 0)

A mixture of 19.0 g of chloramide from section (c) and 12.0 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 250 mL of methylene dichloride was refluxed for two days. The product was separated, purified by silica gel and recrystallized from ether to afford 10.0 g of 5-{-5-[2-bromo-6-chloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole, mp 41 °C . . . 42 °C.

The following Examples 25 . . . 29 were prepared using procedures analogous to those described in Example 24.

Example 25 a) Methyl 3-chloro-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}- 5-nitrobenzoate

(X; Y = (CH₂)₅, Z = N, R = CH₃, R₁ = Cl, R₂ = NO₂, Alk = CH₃), m.p. 65 ºC. . . 67 ºC (from t-butyl methyl ether)

The intermediate methyl 3-chloro-4-hydroxy-5-nitrobenzoate was a yellow solid, m.p. 118 ºC . . . 119 ºC (from carbon tetrachloride).

b) 3-chloro-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}-5- nitrobenzoic acid

(XI; Y = (CH2)5, Z = N, R = CH3, R1 = Cl, R2 = NO2), m.p. 94ºC 95ºC (from hexane-isopropyl acetate).

c) 3-Chloro-N-(2-chloroethyl)-4-{[(5-(3-methyl-5-isoxazolyl)pentyl]oxy}-5-nitrobenzamide

(III; X = 0, Y = (CH₂)₅, Z = N, m = 0, R = CH₃, R₁ = Cl, R₂ = NO₂, R₃ and R₄ = H, Hal' = Cl), m.p. 73 ºC . . . 74 ºC (from t-butyl methyl ether).

d) 5-{5-[2-chloro-4-(4,5-dihydro-2-oxazolyl)-6-nitrophenoxy]pentyl}-3-methylisoxazole

(II; R = CH₃, R₁ = Cl, R₂ = NO₂, R₃ and R₄ = H, m = 0), viscous yellow oil after chromatography.

Example 26 a) 3-Chloro-5-methyl-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}benzoic acid

(XI; Y = (CH₂)₅, Z = N, R = CH₃, R₁ = Cl, R₂ = CH₃), m.p. 98 ºC . . . 99 ºC (from ether-hexane)

The above compound was prepared from 3-chloro-4-hydroxy-5-methylbenzaldehyde, brownish-orange flakes, m.p. 114 ºC . . . 116 ºC (prepared from 2-chloro-6-methylphenol and hexamethylenetetramine in trifluoroacetic acid), by alkylation with 5-(5-bromopentyl)-3-methylisoxazole to give 3-chloro-5-methyl-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}benzaldehyde and oxidation of the latter with silver nitrate.

b) 3-chloro-N-(2-chloroethyl)-5-methyl-4-{[5-(3-methyl-5- isoxazolyl)pentyl]oxy}benzamide

(III; X = 0, Y = (CH₂)₅, Z = N, m = 0, R = CH₃, R₁ = Cl, R₂ = CH₃, R₃ and R₄ = H, Hal' = Cl), F 84 ºC . . . 85 ºC (from ether)

c) 5-{5-[2-chloro-4-(4,5-dihydro-2-oxazolyl)-6-methylphenoxy]pentyl}-3-methylisoxazole

(II; R = CH₃, R₁ = Cl, R₂ = CH₃, R₃ and R₄= H, m = 0), colorless liquid.

Example 27 a) 3-chloro-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}-5- trifluoromethylbenzoic acid

(XI; Y = (CH₂)₅, Z = N, R = CH₃, R₁ = Cl, R₂ = CF₃)

The above compound was prepared by chlorination of 3-trifluoromethyl-4-hydroxybenzonitrile, alkylation of the latter with 5-(5-iodopentyl)-3-methylisoxazole to produce 3-chloro-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}- 5-trifluoromethylbenzonitrile, followed by hydrolysis of the nitrile group to a carboxy group.

b) 3-Chloro-N-(2-chloroethyl)-4-{[5-(3-methyl-5-isoxazolyl)phenyl}-5-trifluoromethylbenzamide

(III; X = 0, Y = (CH₂)5, Z = N, m = 0, R = CH₃, R�1 = Cl, R₂ = CF₃, R₃ and R₄ = H, Hal¹ = Cl)

c) 5-{5-[2-chloro-4-(4,5-dihydro-2-oxazolyl)-6-(trifluoromethyl)phenoxy]pentyl}-3-methylisoxazole

(II; R = CH₃, R₁ = Cl, R₂ = CF₃, R₃ and R₄ = H, m = 0), pale yellow liquid by chromatography.

Example 28 a) 3,5-Dichloro-N-(3-chloropropyl)-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}benzamide

(III; X = 0, Y = (CH₂)₅, Z = N, m = 1, R = CH3, R₁ and R₂ = Cl, R₃ and R₄ = H, Hal' = Cl), colorless needles, mp 72ºC . . . 73ºC.

b) 5,6-Dihydro-2-{4-[5-(3-methyl-5-isoxazole)pentyloxy]phenyl}-4H-1,3-oxazine

(II; R = CH₃, R₁ and R₂ = Cl, R₃ and R₄ = H, m = 1), colorless oil.

Example 29 a) Methyl 3,5-dichloro-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}benzoate

(X; Y = (CH₂)₅, Z = N, R = CH₃, R₁ and R₂ = Cl, Alk = CH₃), pale yellow oil, by chromatography.

b) 3,5-Dichloro-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}benzoic acid

(XI; Y = (CH2)5, Z = N, R = CH3, R1 and R2 = Cl), F 77 ºC 79 ºC.

c) 3,5-Dichloro-N-(2-chloroethyl)-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}benzamide

(III; X = 0, Y = (CH₂)₅, Z = N, m = 0, R = CH₃, R₁ and R₂ = Cl, R₃ and R₄ = H, Hal' = Cl), M 88 ºC . . . 90 ºC.

d) 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole

(II; R = CH₃, R₁ and R₂ = Cl, R₃ and R₄ = H, m = 0)

To a solution of 1.0 g of 3,5-dichloro-N-(2-chloroethyl)-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}benzamide in 75 ml of methylene dichloride was added 0.92 g of 1,8-diazabicyclo[5.4.0]undec-7-ene and the mixture was heated under reflux for 16 hours. The The reaction mixture was concentrated in vacuo and the residue partitioned between 150 mL of ethyl acetate and 50 mL of water. The organic layer was separated, washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed over silica gel and eluted with 1:1 ethyl acetate:hexane. The eluted material was isolated, dissolved in ether and crystallized after seeding to afford 0.60 g (<66%) of the compound 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole as a light yellow solid, mp 39 ºC...40 ºC, which was found to be identical to the compound of Example 1(c) by thin layer chromatography.

Example 30 a) Ethyl 3,5-dichloro-4-[6-(3-methyl-5-isoxazolyl)hexyl]benzoate

(XIV; Y = (CH₂)₅, Z = N, R = CH₃, R₁ and R₂ = Cl, Alk = C₂H₅)

To a solution of 1.2 mL of hexamethylphosphoramide and 6.7 mL of 1.75 in lithium diisopropylamide in 9 mL of tetrahydrofuran at 0 ºC under nitrogen was slowly added a solution of 1.00 g of 3,5-dichloro-4-methylbenzoic acid in 3 mL of tetrahydrofuran. After one hour, the solution was cooled to -78 ºC and 1.00 g of 5-(5-bromopentyl)-3-methylisoxazole was added. The reaction mixture was stirred at room temperature for 19 h and further processed by acid/base extraction to give 1.3 g of a crude acidic product. The latter was treated with 1 mL of ethyl iodide and 4.9 g of potassium carbonate in 10 mL of dimethylformamide and stirred at room temperature for 12 h. Extraction with ether and washing with water afforded 1 g of ethyl 3,5-dichloro-4-[6-(3-methyl-5-isoxazolyl)hexyl]benzoate, which was suitable for the subsequent reactions.

b) 5-{6-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenyl]hexyl}-3-methylisoxazole

(I; X = CH₂, Y = (CH₂)₅, Z = N, R = CH₃, R₁ and R₂ = Cl, R₃ and R₄ = H)

A solution of 2.6 g of ethyl 3,5-dichloro-4-[6-(3-methyl-5-isoxazolyl)hexyl]benzoate and 0.21 g of lithium hydroxide in 30 mL of methanol and 10 mL of water was heated under reflux for 12 hours. Work-up afforded 2.2 g of the corresponding benzoic acid, which was stirred with 2 mL of thionyl chloride in chloroform for 14 hours. The mixture was concentrated and added to a solution of 1.00 g of ethanolamine in 50 mL of methylene dichloride. Flash filtration afforded the 2-hydroxyethylamide (1.7 g) as a yellow solid. The latter was converted to its methanesulfonate ester with 0.33 mL of methanesulfonyl chloride and 0.7 mL of triethylamine in methylene dichloride, the said mesylate being dissolved in 100 mL of acetonitrile containing 1.0 g of 1,8-diazabicyclo[5.4.0]undec-7-ene and heated under reflux for 4 hours. Concentration and rapid filtration afforded 1.0 g of 5-{6-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenyl]hexyl}-3-methylisoxazole as a colorless solid, mp 65 °C . . . 66 °C after recrystallization from isopropyl acetate-hexane.

Alternatively, the intermediate 2-hydroxyethylamide was treated with thionyl chloride to give N-(2-chloroethyl)-3,5-dichloro-4-[6-(3-methyl-5-isoxazolyl)hexyl]benzamide (III; X = CH2, Y = (CH2)5, Z = N, m = 0, R = CH3, R1 and R2 = Cl, R3 and R4 = H, Hal' = Cl), after which the latter was converted by ring closure to the final product.

The biological evaluation of the compounds of formulas I and III has shown that they have antiviral activity. They can be used in vitro to inhibit virus replication and are mainly active against picornaviruses, in particular against numerous types of rhinoviruses. The in vitro tests of the compounds of formulas I and III have shown that they have antiviral activity. Invention against picornaviruses showed that viral replication was inhibited at minimum inhibitory concentrations (MIC) ranging from about 0.003 to about 3 micrograms per milliliter.

MIC values were determined in a standard plaque dilution assay as follows: HeLa cells (Ohio) were infected in monolayers with a concentration of virus to yield approximately 80 plaques per monolayer in the virus control (no drug present). The compound to be tested was serially diluted and included in the top layer of the agar medium and, in some cases, during the adsorption period. The MIC was determined as the concentration of compound that reduced plaque number by 50% compared to the untreated virus control.

In the standard test procedure, the compounds were tested against a panel of 15 human rhinovirus (HRV) serotypes, namely HRV-2, -1A, -1B, -6, -14, -21, -22, -15, - 25, -30, -50, -67, -89, -86 and -41. The MIC value for each rhinovirus serotype was determined and the potency of each compound was determined as a MIC80 value, which indicates the concentration of the compound required to inhibit 80% of the serotypes tested.

In the in vivo studies, Swiss white mice, weighing an average of 20 g, were infected with 2 LD50 of polio virus, type 2, MEF strain by injection of 0.03 ml of virus (540 PFU, plaque forming units) into the left cerebral hemisphere. Mice were treated intergastrically with the test compound as a suspension in gum tragacanth for one hour before infection, 6 hours after infection, and twice daily thereafter for a total of 10 days. Placebo-treated mice were included in the test, with all mice monitored twice daily for death. Tests were completed 15 days after infection.

The blood plasma concentrations of the compounds of Invention were measured in beagle dogs using the following procedure: Animals weighing in the range of 8.5 to 11.5 kg were given an oral administration of 25 ml/kg of the test compound dissolved in corn oil (125 mg/ml) and contained in gelatin capsules after an overnight fast. Blood samples were collected at selected time intervals up to 6 hours after administration and analyzed by standard chromatography procedures to determine the mean maximum concentration of the test compound in micrograms per milliliter (mean Cmax, ug/ml).

The following table shows the test results with the compounds according to the invention. A. Compounds of formula I Example No. MIC (Polio 2) MIC80 (Rhinovirus) Plasma concentration (dog) mean Cmax, ug/ml A. Compounds of formula I (cont.) Example No. MIC (Polio 2) MIC80 (Rhinovirus) Plasma concentration (dog) mean Cmax, ug/ml B. Compounds of formula III Example No. MIC (Polio 2) MIC80 (Rhinovirus)

IA . . . ineffective

(a) . . . only against HRV-2

(b) . . . against 5 HRV serotypes

(c) . . . against 6 HRV serotypes

NT . . . not yet tested

The compound of Example 1 (c) 5-{5-[2,6-dichloro- 4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole was tested in mice against polio virus-2 with the following results:

Survivors - 14 days after infection

50 mg/kg/day 2/20

100 mg/kg/day 5/20

200 mg/kg/day 6/20

Placebo1/20

In several cases, the compounds of formulas I and II have been found to have improved antirhinovirus MIC80 values and/or plasma concentration Cmax values compared to the corresponding compounds having only one substituent or no substituent on the phenyl ring adjacent to the X bond.

This improvement is particularly evident when comparing the test results with the following three compounds:

A. 5-{5-[2,6-Dichloro-4-(4,5-dihydro-2-oxazolyl)phen oxy]pentyl}-3-methylisoxazole (Example 1c)

B. 5-{5-[2-chloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole (EP-A-137,242, Example 15b)

C. 5-{5-[4-(4,5-Dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole (EP-A-137,242, Example 2c). Connection MIC80 Cmax

(a) against 53 rhinovirus serotypes

(b) against 15 rhinovirus serotypes

In another case, the compound of Example 2, 5-{-5-[4-(4,5-dihydro-2-oxazolyl)- 2,6-dimethylphenoxy]pentyl}-3-methylisoxazole, was found to have a Cmax value for blood plasma concentration of 4.26 ± 0.47, while the corresponding analogous monomethyl compound, 5-{5-[4- (4,5-dihydro-2-oxazolyl)-2-methylphenoxy]pentyl}-3-methylisoxazole, had a Cmax value of only about 0.50.

Other compounds that have unusually high antirhinovirus activity in vitro are those of Examples 9, 24(d) and 26 (see Table above).

The antiviral compositions are prepared for use by presenting a diluted solution or suspension in a pharmaceutically acceptable aqueous, organic or aqueous-organic medium for parenteral administration by intravenous or intramuscular injection or for intranasal or ophthalmic administration, or in tablets, capsules or in the form of an aqueous suspension or with conventional excipients for oral administration.

Claims (6)

1. Connection the formula in which are: R is hydrogen or alkyl having 1 to 3 carbon atoms optionally substituted by hydroxy or alkoxy having 1 to 4 carbon atoms; X is O or CH₂; Y is an alkylene bridge with 3 to 9 carbon atoms or an olefin chain of 5 carbon atoms with an unsaturated bond; Z is N or R₅C, wherein R₅ is hydrogen or an alkanoyl of 1 to 4 carbon atoms, provided that R is not hydrogen when Z is N; in O or 1; R₁ and R₂ are each halogen, methyl, nitro or trifluoromethyl and R₃ and R₄ each represent hydrogen or lower alkyl having 1 to 3 carbon atoms or their pharmaceutically acceptable acid addition salts. 2. A compound according to claim 1 of the formula in which are: in O or 1; R is methyl or hydroxyethyl; R₁ and R₂ are each halogen, methyl, nitro or trifluoroethyl and R₃ and R₄ each represent hydrogen or lower alkyl having 1 to 3 carbon atoms or their pharmaceutically acceptable acid addition salts. 3. A compound according to claim 2, 5-{5[2,6-dichloro-4(4,5- dihydro-2-oxazolyl)phenoxy]pentyl}isoxazole or its pharmaceutically acceptable acid addition salt. 4. Connection of the formula in which are: Hal' chlorine or bromine; X is O or CH₂; Y is an alkylene bridge with 3 to 9 carbon atoms ZN or R₅C, wherein R₅ is hydrogen or alkanoyl of 1 to 4 carbon atoms in O or 1; R₁ and R₂ are each halogen, methyl, nitro, lower alkoxycarbonyl having 1 to 4 carbon atoms or trifluoromethyl and R, R₃ and R₄ are hydrogen or lower alkyl having 1 to 3 carbon atoms, provided that R is lower alkyl having 1 to 4 carbon atoms when Z is N. 5. Composition for combating viruses comprising an amount of a compound having antiviral activity according to any one of claims 1 to 4 in admixture with a suitable carrier or diluent. 6. Process for preparing a compound of formula in which are: X is O or CH₂; Y is an alkylene bridge with 3 to 9 carbon atoms or an olefin chain of 5 carbon atoms with an unsaturated bond; Z is N or R₅C, wherein R₅ is hydrogen or lower alkanoyl of 1 to 4 carbon atoms, provided that R is alkyl of 1 to 3 carbon atoms when Z is N; m O or 1; R is hydrogen or alkyl having 1 to 3 carbon atoms, optionally substituted by hydroxy or lower alkoxy having 1 to 4 carbon atoms; R₁ and R₂ are halogen, methyl, nitro or trifluoromethyl and R₄ and R₄ are hydrogen or lower alkyl having 1 to 3 carbon atoms, which includes: (a) preparing a compound without a double bond in the 4,5-position of the oxazole or 5,6-oxazine ring and wherein R is hydrogen or lower alkyl having 1 to 3 carbon atoms and upon ring closure a compound of the formula is formed, in which Hal' is chlorine or bromine, by heating the latter in an inert solvent in the presence of an acid acceptor, excluding compounds in which Y is an alkylene bridge interrupted by an olefin chain; or (b) preparing a compound wherein X is O by reacting a compound of the formula where Hal is chlorine, bromine or iodine, are reacted with an alkali metal salt of a compound of the formula and optionally etherifying a compound of formula I, wherein R is hydroxyalkyl, by reacting it with a lower alkyl halide in the presence of a strong base to provide a compound in which R is lower alkoxylower alkyl and means "lower" C1 to C4; and optionally converting a resulting basic compound to its acid addition salt.